State of the Art in the Treatment of Medulloblastoma/Primitive Neuroectodermal Tumors with Radiation Therapy

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Innovations in the treatment of Primitive Neuroectodermal Tumors
(PNET) and Medulloblastoma (MB) with Radiation Therapy (RT) have
run hand-in-hand with those in the surgical, chemotherapeutic,
and diagnostic spheres. Improvements in radiotherapy equipment
and techniques along with the use of altered fractionation schemes,
the optimization of radiation doses, and the administration of
other adjuvant therapies have all contributed to improvements
in outcome. Results, however, are not measured by survival alone.
The long term toxicity that may arise from the administration
of therapy can be considerable, and treatment must be adjusted
accordingly. Thus, in the last decade, refinements in treatment
have focused as much on improvements in quality of life as on
survival.

Toxicity caused by craniospinal radiation therapy (CSART) can
be formidable, especially in the youngest children. (17, 19)
Efforts have been directed at reducing this toxicity by lowering
the CSART dose. These reductions have come in the face of some
series demonstrating the necessity for doses above 3000 cGy (14, 16, 18) and others demonstrating favorable outcomes in select children treated with considerably lower doses (5, 12, 15).

As a consequence of these experiences, a Pediatric Oncology Group
(POG)/Children's Cancer Group (CCG) study was launched pitting
reduced craniospinal radiation doses (2340 cGy) against standard
radiation (3600 cGy) for patients with low stage disease. This
trial closed prematurely due to an increased number of failures
in the reduced-dose arm. With time, the differences between the
two arms have become less significant, though improved survival
is still seen in the full-dose arm (6). In parallel,
an unsuccessful attempt at the complete elimination of the whole
brain component of the CSART was made in the SIOP the SIOP M4
trial. Results were disappointing, with only 3 of 16 children
surviving. (4).

Thus, for patients with medulloblastoma treated with RT alone,
spinal and supratentorial RT is mandatory, as is the posterior
fossa boost. The craniospinal dose is typically 3600 cGy in 20
fractions, and the dose to the posterior fossa 5400-5580 cGy.
Survival after such treatment ranges between 40 and 90% at 5 years,
depending on a variety of factors including age, stage and extent
of surgical resection. (6, 8, 14, 20, 22)

Chemotherapy is now used routinely in all children with advanced
disease. The justification is based on randomized trials from
the U.S. and Europe comparing radiation alone with radiation plus
chemotherapy. (8, 22) In both of these series,
CCNU, Vincristine (and Prednisone, for the U.S. series) were shown
to improve survival for children with leptomeningeal disease and
advanced local disease.

Platinum-based chemotherapy regimens are now widely utilized.
Platinum is highly active against recurrent MB/PNET (9)
as well as newly-diagnosed cases (20) In a series
from the Children's Hospital of Philadelphia (20),
children with "high risk" medulloblastoma were treated
with cis-platinum based chemotherapy following surgery and radiation therapy. In some of the younger children, reduced craniospinal
doses were used. Survival for the "high risk" children,
ordinarily reported to be less than 50% at 5 years, was is reported
to be nearly 90%. A CCG pilot study utilizing 2340 cGy plus the
same platinum-based chemotherapy accrued nearly 80 patients in
the 2 years it was open. Thus far, actuarial survival ranges above
80% at 3 years (Personal Communications, Roger Packer, MD).

For low-stage patients, the role of chemotherapy remains complex.
As a consequence of the excellent results reported for high-stage
patients treated with adjuvant platinum-based chemotherapy, an
effort was made to study the regimen in conjunction with reduced
doses of radiation for children with low-stage disease. Indeed,
a pilot study of 10 children treated with 1800 cGy to the craniospinal
axis, a posterior fossa boost, and platinum-based chemotherapy
achieved long term survival of 70%, without the profound neurocognitive
toxicity normally associated with higher doses (11).
Ultimately, a POG/CCG trial randomized low-stage patients to either
standard RT alone (3600 cGy) or reduced-dose craniospinal axis
RT (2340 cGy) plus chemotherapy. The trial remained open for two
years but was terminated prematurely because of poor accrual.
Too few patients were entered to address any of the study questions.
Finally, a recently reported trial mounted by SIOP demonstrated
disappointing results from the administration of chemotherapy
and reduced dose radiotherapy, with a 5-year actuarial survival
of 42% (3). Thus, the question as to whether low-stage
medulloblastoma patients benefit from reduced-dose RT plus chemotherapy
remains unanswered.

In parallel with reductions in radiation doses, radiation fields
have been tailored and refined to conform better to the volumes
at risk for disease. These refinements, in turn, have been based
on improvements in imaging techniques which have allowed for better
definition of the inferior extent of the thecal sac (13)
and improved definition of the posterior fossa (21).
Whether the improvements in RT techniques will result in decreased
toxicity is not yet known.

Hyperfractionated radiotherapy is currently under study for children
with supratentorial PNET and high stage medulloblastoma. (CCG-9931.
CCG Meeting Book, November 1996). Objectives are to increase control
in advanced-stage patients by increasing the radiation dose without
increasing associated late toxicity. While single institutional
series of children treated with hyperfractionated RT have been
published (2, 23), effective comparison with conventional therapy will require larger studies performed over longer periods of time.

Babies with PNET and Medulloblastoma pose a particular challenge
to the neuro-oncology team. Such patients are eminently more susceptible
to the devastating side effects of radiation therapy, and may
have biologically more aggressive lesions (1).
Results of two prominent series of children treated with neoadjuvant
chemotherapy have been reported (7, 10).
Patients under the age of three were eligible for entry, and radiotherapy was delayed to the time of progression, to completion of chemotherapy, or to the age of three years depending on the circumstances for the particular patient. In the Geyer series, most children were not treated with radiotherapy as had been prescribed, while in
the Duffner series, they were. Results have been discouraging,
with event-free survival at 3 years of 32% or less for the children
with medulloblastoma, and 19% or less for those with PNET.

Even though the last decades have seen remarkable innovations
in the use of radiotherapy against these diseases, room for improvement
remains. Advances will need to be directed at increasing survival
and decreasing toxicity. Identifying the subgroups of children
who require higher doses of radiation, or who can most benefit
from altered fractionation and reduced doses will be one of our
greatest challenges. Conforming our radiation beams to the volumes
at risk, and minimizing doses to normal tissues will be another.

Aug 2, 2012 - Compared with postoperative chemotherapy alone, adding conformal radiation therapy to induction chemotherapy for the treatment of young children with nonmetastatic medulloblastoma increases event-free survival, according to a study published online July 30 in the Journal of Clinical Oncology.